Sucralose, 4,1′,6′-trichloro-4,1′,6′-trideoxygalactosucrose, a sweetener with a sweetness intensity several hundred times that of sucrose, is derived from sucrose by replacing the hydroxyl groups in the 4, 1′, and 6′ positions with chlorine. Synthesis of sucralose is technically challenging because of the need to selectively replace specific hydroxyl groups with chlorine atoms, while preserving other hydroxyl groups including a highly reactive primary hydroxyl group. Numerous approaches to this synthesis have been developed. See, e.g., U.S. Pat. Nos. 4,362,869; 4,826,962; 4,980,463; and 5,141,860, which are expressly incorporated by reference herein. However, such approaches typically provide a product that contains varying levels of other chlorinated sugar compounds in addition to sucralose. Increasingly, efforts have been directed toward the isolation of sucralose in highly pure form from this complex mixture of related chlorinated materials. Early reported work typically involved crystallizing sucralose directly from the synthesis mixture, a process that yields a material with high impurity levels. Sucralose is sometimes purified from a synthesis mixture by silica gel chromatography. See, e.g., U.S. Pat. No. 5,128,248, which is expressly incorporated by reference herein. That procedure, due to its use of silica gel, may be ill-suited to large-volume commercial production of highly pure sucralose. In addition, relatively little attention has been focused on other approaches for removing chlorinated sugar impurities from sucralose. Efficient removal of these impurities is important because, even at quite low concentrations, they can have an adverse impact on the sweetness, taste, and flavor-modifying properties of sucralose.
The synthesis of sucralose typically results in the concomitant synthesis of a range of chlorinated sucrose moieties which need to be separated and removed from the target molecule (sucralose) during the manufacturing process. Typically, after preparation, the sucralose containing feed stream is subjected to a number of purification steps, of which solvent extraction is one purification process typically employed for the removal of species less and more hydrophobic than sucralose itself.
Various methods for the synthesis of sucralose and related compounds have been suggested. U.S. Pat. No. 4,405,654, which is expressly incorporated by reference herein, for example, relates to a process for the synthesis of a related compound, 1′,4′,6′-trichloro-1′,4′,6′-trideoxysucrose. After the deacetylation of a pentaacetate precursor, the reaction mixture is purified by column chromatography on silica gel. The product is eluted from the silica gel with ethyl acetate.
U.S. Pat. No. 4,980,463, which is expressly incorporated by reference herein, relates to a process in which sucralose is produced by KOH treatment of a methanol solution of sucralose-6-benzoate. The methanol is removed by evaporation, and the residue is dissolved in water. The aqueous solution is extracted three times with separate one-quarter volumes of ethyl acetate. The combined organic extracts are concentrated and then back extracted with water to recover sucralose present in the ethyl acetate. The combined aqueous portions are concentrated and treated with a decolorizing agent. Additional concentration permits crystallization of the sucralose. The recovered crystals have a reported purity of 99.6%. Purification to this level is achieved primarily through crystallization, rather than by solvent extraction processes. It is noteworthy that this approach only involves ethyl acetate extraction of the original aqueous solution, and sucralose is never re-extracted from the aqueous solution into an organic phase, thereby achieving a further purification.
U.S. Pat. No. 5,034,551, which is expressly incorporated by reference herein, relates to a similar process in which a base is used to hydrolyze a solution of sucralose-6-benzoate in methanol. The methanol is removed by evaporation, and the sucralose-containing residue is dissolved in water. This solution is extracted three times with separate one-quarter volumes of ethyl acetate. The remaining aqueous layer is decolorized with charcoal and concentrated, and the sucralose is allowed to crystallize.
U.S. Pat. No. 5,498,709, which is expressly incorporated by reference herein, relates to solvents that may be used to extract sucralose from the aqueous brine produced by alkaline hydrolysis of a 6-acyl ester precursor compound. Possible solvents include methyl acetate, ethyl acetate, methyl ethyl ketone, methyl isobutyl ketone, methyl isoamyl ketone, methylene chloride, chloroform, diethyl ether, and methyl tertiary butyl ether. Ethyl acetate is presented as a suitable solvent for reasons of extraction selectivity, ease of recycling, and toxicological safety.
U.S. Pat. No. 5,498,709 also relates to a process in which the aqueous solution remaining after ester hydrolysis of sucralose precursors is concentrated and then sucralose is isolated by three sequential extractions with ethyl acetate or other suitable solvent. The extracts may then be combined, and optionally washed with water to remove any dimethylformamide remaining prior to recovering the sucralose by concentration and crystallization. This patent also relates to processes in which sucralose contained in the aqueous brine obtained after alkaline deesterification is extracted into a solvent not miscible with brine, such as dichloromethane, chloroform, 2-butanone, cyclohexanone, or ethyl acetate. The organic extracts may then be back extracted with water to transfer the sucralose back into the aqueous phase. This aqueous solution may then be decolorized and concentrated, and the resulting purified sucralose is recovered by crystallization. This approach yields a relatively impure material.
An additional approach discussed within U.S. Pat. No. 5,498,709 involves the toluene extraction of the alkaline solution remaining after deesterification. Specifically, the solution is extracted twice with toluene to remove non-polar impurities. The aqueous solution is then extracted repeatedly with 2-butanone. The 2-butanone extracts are combined, and the solvent is evaporated to yield a reddish syrup containing sucralose.
U.S. Pat. No. 5,530,106, which is expressly incorporated by reference herein, relates to an extractive process for a crude sucralose solution obtained after alkaline hydrolysis of sucralose-6-acetate and subsequent neutralization. The aqueous sucralose solution is extracted with water saturated ethyl acetate. Some impurities are selectively partitioned to the organic phase by this extraction. Subsequently, the ethyl acetate phase is backwashed with water in order to recover a portion of the sucralose that had also partitioned into the organic phase. The aqueous solution and the aqueous backwash are combined, concentrated and decolorized, and the sucralose is recovered by crystallization from the aqueous phase.
U.S. Pat. No. 7,049,435, which is expressly incorporated by reference herein, relates to methods for removing impurities from a composition comprising sucralose and impurities in a first solvent comprising the steps of performing a liquid extraction of the composition with a second immiscible solvent to effect removal of the impurities into the second solvent and performing a second extraction of the composition with a third immiscible solvent to effect the transfer of the sucralose into the third solvent and the retention of the impurities in the first solvent.